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BIG PHYSICS, BIG QUESTIONS –

Genetic ‘switch’ to target skin cancer

By PHYLLIDA BROWN

A novel approach to gene therapy for melanoma has been developed by
British scientists. Early trials of the method could start this year on
people with this aggressive form of skin cancer whose existing treatments
have failed.

The key to the new method, developed by researchers at the Imperial
Cancer Research Fund, is that it exploits a genetic ‘switch’ that flicks
on only in the type of cell affected by melanoma. By hooking up potentially
therapeutic genes to this switch, the researchers hope to target treatments
precisely at the melanoma and leave healthy surrounding tissue alone.

Melanoma now affects 3000 people a year in Britain, 1250 of whom die.
The number of cases is doubling each decade. Surgery is effective against
melanomas that are detected early, but the cancer spreads rapidly and once
this has happened, most treatments fail.

Ian Hart and Richard Vile, scientists at ICRF’s London laboratories,
warn that their work is at a very early stage and gene therapy for melanoma
may not be widely available for another 10 years. But the team believe they
have made a ‘concept jump’ that could eventually extend to other types of
cancer. They publish their work in the journal Cancer Research this week.

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The skin cells that turn cancerous in melanoma are called melanocytes.
They make melanin, the pigment that protects against the Sun’s rays, with
the aid of a key enzyme, tyrosinase. Although the gene for tyrosinase is
present in all cells, it is switched on only in melanocytes – by a ‘switch’
gene. ‘In other cells the switch is off. If tyrosinase is not switched on,
you get no melanin,’ says Vile.

The team reasoned that they might be able to use the switch gene to
activate not just tyrosinase, but a range of other genes too – for example,
genes that would stimulate a stronger immune response to cancer cells. As
long as such genes were attached to the switch, they would act only in melanocytes.
In future, other switches could be identified in other types of tumour cell.

Using a ‘marker’ gene, the team tested the idea in mice. Hart and Vile
hooked up the switch gene to the marker gene and injected the DNA directly
into two types of mouse tumour. In melanoma tumours, the marker gene was
switched on. In other tumours containing no melanocytes, the marker gene
remained inactive. Healthy surrounding tissue was also unaffected.

The next step was to see if useful genes could be switched on by the
same method. The first to be tested was the gene for interleukin-2, a messenger
protein made by cells of the immune system. If melanoma cells can be made
to produce IL-2, this should stimulate a strong, specific immune response
against them. IL-2 has unpleasant side effects if given in large doses,
but targeting it at melanoma cells should be less toxic.

In mice, the team has succeeded in making the IL-2 gene switch on in
melanoma cells. They are now waiting to see whether the animals’ immune
systems destroy the cells.

Doctors led by Adrian Harris at the ICRF’s Clinical Oncology unit in
Oxford will apply next week for permission to test the therapy on a small
group of terminally ill patients. They will inject the switch, hooked up
to IL-2, directly into melanoma secondaries that have spread in their skin.
The team hopes the tumours will shrink, although no cures are expected yet.

In the US, scientists are already experimenting with other forms of
gene therapy for cancer. One method is to remove some tumour cells from
the patient at the time of surgery, insert a gene for an immune-stimulating
protein into them, and return them to the body. Another is to remove killer
T cells from the body, insert a ‘warhead’ gene into them and return them
to the body.